This invention pretains to compositions for and methods of treating muscle degeneration and weakness. More particularly, the present invention relates to myogenic cells and methods of using such cells in the treatment of muscle degeneration and weakness.
Progressive degeneration and weakness of skeletal muscles are hallmarks of the forty human neuromuscular diseases affecting motoneurones, peripheral nerves and/or muscles. Most of these diseases are fatal, and all are crippling. There is no known cure or effective treatment. These diseases include motoneurone disorders, such as Amyotrophic Lateral Sclerosis (ALS) and neuromuscular junction disorders, such as Myasthenia Gravis and Eaton-Lambert Syndrome. Also included are the twelve hereditary muscular dystrophies, predominantly muscle diseases, affecting over 200,000 Americans. In the muscular dystrophies, dystrophic cells degenerate because of the lack of normal genome.
Muscular dystrophy in the mouse is characterized by progressive degeneration of skeletal muscles in the hindlimbs and in the chest wall. Dystrophic symptoms first appear at 20 to 30 days after birth and consist of sporadic flexion and flaccid extension of the hindlimbs. Occasionally, the dystrophic mouse walks with duck feet (See for example, Michelson et al., Proc. Nat. Acad. Sci., 41: 10798, (1955) and Meier et al., Life Sci., 9: 137, (1970)). A number of approaches have been employed by researchers in the field to study and develop methods to treat the muscular dystrophies and other neuromuscular disorders.
In the case of the hereditary neuromuscular disorders, one approach to correct the genetic disease is to correct the abnormal gene itself. However, before gene therapy can be used to treat hereditary myopathies, the defective genes and their expression have to be determined. Although identification of the dystrophic genes and their primary protein abnormalities has been attempted by some workers, thus far, attempts at identification have not been completely successful. (See e.g., Monaco et al., Nature 323: 646-650, 1986; Brown et al., Hum. Genet. 71: 62-74, 1985). Furthermore, before gene therapy can be used to treat hereditary myopathies, the problems of nonspecific gene integration, replacement, targeting, regulation and expression also have to be overcome. The high spontaneous mutation rate also complicates the process of identification and prevention. (See e.g., Epstein et al., Am Sci 65: 703-711, 1977.) When normal and dystrophic tissues are compared, the dystrophy-specific protein difference is often masked by the concomitant presence of individual-specific protein differences (see, e.g., Komi et al., Acta. Physiol. Scand. 100:385-392, 1977) and secondary degenerative changes (See, e.g., Dolan et al., Exp. Neurol. 47:105-117, 1975). In situations where the primary protein abnormality is not known, any trial of drugs to treat the disease will necessarily be arbitrary and its success coincidentally limited. (See, e.g., Bhargava et al., Exp. Neurol. 55:583-602, 1977.)
In Duchenne muscular dystrophy, carrier detection and prenatal diagnosis seek prevention rather than cure. See, e.g., Bechmann, Isr. J. Med Sci 13:102-106, 1977. These are inadequate measures, because not all sex-linked carriers--inasmuch as they are phenotypically normal--are exposed to the diagnostic tests. There are also the legal, religious, emotional and financial considerations involved in inducing an abortion.
Various studies have been carried out in attempts to develop methods to treat neuromuscular disease.
In one reported approach, mouse muscle mince transplants studies were conducted on normal and dystrophic littermates (Law, Exp. Neurol., 60:231, 1978). In another study, it is reported that near-normal contractile properties were produced in adult dystrophic mouse muscle by grafting a muscle of a newborn normal mouse into a recipient muscle of a dystrophic mouse (Law et al., Muscle & Nerve, 2:356, 1979). It is also been reported that mesenchyme transplantation can improve the structure and function of dystrophic mouse muscle as demonstrated by histological, electrophysiological and mechanophysiological studies (Law, Muscle & Nerve, 5:619, 1982).
Watt et al., Muscle and Nerve, 741-749, Nov/Dec, 1984, report the injection of normal myoblasts into apparently abnormal muscle of strain mdx mice, but do not report any improvement in muscle function, The mdx mice do not exhibit any muscle weakness. Myoabnormality of central nucleation heals itself with age.
It has further been reported that injections of normal myoblasts into growing dystrophic mouse solei improved the structure and function of the solei (Law and Goodwin, Fifth Biennial Forum Regeneration Abst, 1985, page 18; Law and Goodwin, Soc. Neurosi. Abst. 11:212, 1985; and Law and Goodwin, IV International Congress on Neuromuscular diseases, Abst. 9, 1986). Improved muscle function was determined only by electrophysiological and mechanophysiological studies. In such studies, only one muscle, the soleus, rather than all major muscle groups were tested. The soleus, containing many red fibers that are slow twitching, is unique and different from other muscles in the body that are composed of fast twitching fibers.
Various attemps have been made to provide treatments for neuromuscular disorders. However, none have achieved recovery of muscle function, locomotive pattern and respiratory function in a host affected with muscle degeneraion and weakness. Thus, compositions and methods of treating such disorders are being sought.